Phosphatide therapeutic composition and method of treatment therewith



United States Patent Royall M. Calder, San Antonio, Tex.

No Drawing. Application February 25, 1959 Serial No. 795,364

7 Claims. (Cl. 167-65) This invention relates to medicinal compositionsuse ful for treating osteoarthritis and to a process of treating humanshaving osteoarthritis. More particularly, this invention relates to suchcompositions in which the active ingredient is the acetone-insolublefractions of phosphatides of corn or maize and to the method ofcontrolling osteoarthritis in humans with such compositions.

The disorder, osteoarthritis, is known by a number of synonyms,including hypertrophic arthritis, degenerative joint disease, senescentarthritis, degenerative arthritis, and arthritis deformans. It is achronic disabling disease affecting at least twenty-five million peoplein this country, of whom more than a million are so badly afflicted asto require medical attention in any given year.

The pathological and clinical features of the disease are well describedin standard textbooks of medicine and arthritis. The process begins withdegeneration of articular cartilage, the normal function of which is tocushion the ends of bones where they come together as a joint.Subsequently a series of secondary changes occur which are reparativeand compensatory in nature. These changes include hypertrophy andincreased vascularity in the surrounding fibrous or periarticularstructures; increase in number and size of the villi of the synovialmembrane, which may contain cartilage, may be partially ossified, or mayeven break off to form loose bodies (joint mice) in the joint; and,ultimately, complete destruction of the articular cartilages, withexposure of the underlying bone, which becomes very dense, polished andhard or eburnated.

The disease may attack any joint or joints. Those subject to frequentuse; such as, for example, the fingers; or to weight: such as, forexample, the spine, hips and knees are most commonly involved. Itfrequently affects the terminal joints of the fingers, especially inwomen after the menopause, and the enlargement so produced is known asHeberdens nodes.

The basic cause of the degeneration of articular cartilage identified asosteoarthritis is unknown in most cases.

In some instances, antecedent destructive factors may be obvious; suchas, for example, acute or chronic occupational or postural traumata, andprevious inflammatory or infectious processes, such as rheumatoid, goutyor suppurative arthritis. Such cases have been appropriately classifiedas, secondary osteoarthritis. But, in the great majority ofcases, thereason for the deterioration of these articular cartilages is completelyobscure and such cases are classified as primary osteoarthritis.Observant physicians have long suspected that the disease is associatedwith a predisposing hereditary factor, and Stecher'and his associates,by statistical analyses, have demonstrated a familial tendency to thedevelopment of this type of rheumatism, at least insofar as theincidence of Heberdens nodes is concerned. Even granted that such anhereditary vulnerability of articular cartilage exists, the actualprecipitating cause or causes of the destructive changes'remain unknown.Other work in this field which is exemplary was that of Wollenberg, whohas shown experimentally that interference with the circulation to thejoint is followed by hypertrophy of bone. Pemberton and associatesconfirmed and extended this finding. Such observations have not,however, led to any recognized treatment of the disease.

Heretofore, no specific treatment for osteoarthritis was available, withthe exception, in recent years, of therapy involving the use ofcortisone and its derivatives or analogues. While a symptomaticimprovement in the treatment of this disease with such drugs has beennoted, the latter preparations provoke so many deleterious side effects,particularly in the aged, that their use is not recommended except byintra-articular injection. Prior to the foregoing therapy, thetherapeutic efforts in the treatment of the disease have been limited tothe prevention of postural trauma by weight reduction, correction ofobvious deformities by orthopedic procedures, improvement of mobility ofjoints by physiotherapy, and relief of pain by analgesics. In the lattertherapy, phenylbutazone (3,5- dioxo-1,2-diphenyl-4-n-buty1.pyrazolidine) is the most effective analgesic employed, but it is tootoxic to permit prolonged administration.

The lack of therapeutic compositions for treating osteoarthritis whichare non-toxic and which do not produce deleterious side efiects isovercome by this invention which is based on the discovery that thedisease may be effectively treated with a therapeuttic composition inwhich the active ingredient consists of the acetone-insoluble fractionsof the phosphatides from corn or maize. More particularly, thisinvention is based upon the discovery that osteoarthritis may beeffectively treated by administering a novel dosage unit form-of theacetone-insoluble fractions of corn or maize phosphatides obtained byprecipitation from corn or maize oil produced by hot or cold pressing ofthe seed of the grain. The principal object of this invention is toprovide nontoxic therapeutic compositions for treating osteoarthritis inhumans to alleviate the pain in effected joints and to increase themotion, flexibility and mobility of such joints. Another object of thisinvention is to provide therapeutic compositions for treatingosteoarthritis in humans wherein the active ingredient consists of theacetone-insoluble fractions of the phosphatides of corn or maize'oil. Afurther object of this invention is to provide a novel dosage unit formof a therapeutic composition for treating osteoarthritis in humanswherein the active ingredient of the compositions consists of theacetone-insoluble fractions of phosphatides obtained by precipitationfrom corn or maize oil produced by hot or cold pressing of the seeds ofsuch grain. Still another object of this invention is to provide aprocess of treating osteoarthritis in humans which comprisesintroducing, by oral administration, into the system of a human affectedby the disease, a novel dosage unit form of a therapeutic compositioncontainingas its active ingredient the acetone-insoluble fractions ofphosphatides precipitated from corn or maize oil produced by hot or coldpressing of the seeds of such grains.

The phosphatides employed in this invention belong to a complex class ofsubstances, the physiological function of which is largely a matter ofspeculation. Phosphatides are classed as compound lipides and arecharacterized by the fact that they invariably contain a phosphoric acidresidue, fatty the source of the phosphatides, alcohols; inositol,capable of functioning as a base; choline, aminoethyl alcohol or whichare often associated in nature with the phosphaone or more polyhydricsuch as, for example,

tides, are also compound lipides,'such as the cerebrosides,"

Patented May 3, 196i] acids which vary according tosuch as, for example,glycerol, sphingosine or and a nitrogenous moiety that is either basicor serine. Glycolipides,

in which fatty acids, a carbohydrate, and a nitrogen compound arecombined. Chemical investigation of these complex substances is sodiflicult that full details of their structure are lacking. They are ofextreme importance since they are constituents of practically all livingtissue and constitute a complex form of fat in such tissue. Thephosphatides can be extracted and concentrated from vegetable and animalsources by virtue of the fact that they are insoluble in acetone.

The specific phosphatides employed in this invention are the cornphosphatides which are derived in a relatively crude form as aby-product of the commercial refining of corn oil by the processdisclosed in United States Patent No. 2,150,732, granted March 14, 1939,to Benjamin H. Thurman, the entire disclosure of which patent isincorporated herein by reference. This process, briefly, consists ofcrushing the seed, removing the husks and pressing the residue to form acake and obtain the oil. The oil may be filtered to remove fibrousmaterials and other solids present. It is then treated with a reagentfor the purpose of precipitating the phosphatides which are thenremoved. The reagents employed to precipitate the phosphatides arewater, alcohol, or aqueous solutions of acids, alkalies or salts. A fulldisclosure of this process for obtaining phosphatides from corn oil willbe found in the above-identified patent.

The phosphatides of corn oil produced in the manner described above areknown commercially as wet gum. This wet gum contains almost all of thecoloring matter of the crude oil and has a neutral corn oil content ofabout 50 percent by weight. There are a variety of commercial uses ofthis wet gum including the uses thereof as additives for chocolate andmargarine which have been approved by the United States Food and DrugAdministration. The wet gum is employed in this invention, preferablyafter it is further purified by extrac tion with acetone. The best modecontemplated for preparing the acetone-insoluble fractions of cornphosphatides for use in this invention is set forth in the followingexample:

Example I The active ingredient employed in the compositions used incarrying out this invention is prepared from the phosphatides of corn ormaize oil produced by the process disclosed in US. Patent No. 2,150,732.These crude phosphatides are referred to as wet gum and are knowncommercially under the trademark Vodol. A porcelain receptaclecontaining about 5.5 liters of acetone is provided with a stirringdevice. About 1.6 kilograms of wet gum corn phosphatides (Vodol) iswarmed to about 70 C. to increase its fluidity and then added slowly tothe acetone with stirring. When the addition is completed, the stirringis continued for from about to about minutes. The suspension thusobtained is filtered through a Biichner funnel provided with a clothfilter sheet. The filtrate is collected and combined with those obtainedfrom subsequent fractions in order that the acetone may be recovered bydistillation for reuse. The precipitate obtained is transferred from thefilter and is, again, slowly added with stirring to about 5.5 liters offresh acetone. The stirring is continued for about 45 minutes after theaddition of the precipitate is completed. The suspension obtained isfiltered in the same manner as described above. The transfer of theprecipitate and the extraction thereof in fresh acetone are repeateduntil a total of four extractions, excluding the first, are completed.

After the final extraction and filtration is completed,

the precipitate is pressed in the filter to express as much acetone aspossible from the precipitate. The precipitate is then transferred to aNo. 10 sieve and forced therethrough to break-up the cake ofprecipitate. The lumps of the precipitate thus obtained are spread-ontotrays which are placed in a vacuum desiccator. The conduit between thedesiccator and the vacuum pump is provided .4 with two Dry-Ice traps.The trays remain in the desiccator until the acetone is removed from theprecipitate and the moisture content is reduced to below about 5 percentby weight; and, preferably below about 3 percent by weight. The driedmaterial is then sieved through a No. 20 sieve.

The acetone-insoluble fractions of corn phosphatides obtained in themanner described above are a light yellow amorphous powder which is veryhygroscopic and which oxidizes spontaneously on exposure to air at roomtemperature within a few days, turning brown at room temperatures. Thehygroscopic property is overcome by adding about 2.0 percent by weightof commercial cornstarch to the powder. The tendency of the fractions tooxidize may be overcome by the addition thereto of small amounts of oneof the standard anti-oxidants which are commercially available and whichare used in the food industry. Alternatively, the powder may be storedin air-tight containers, capsules or packets under refrigeration atabout 0 C. The acetone-insoluble fractions 7 of corn phosphatides, whenthus stored, retain their original appearance and therapeutic activityindefinitely. Stability tests conducted with samples stored in theforegoing manner have established that the samples may be preserved foras long as five years. These fractions, prepared as above, are ofunknown constitution, but are known to contain a large percentage oflecithins and cephalins characteristic of corn phosphatides; and, aswell, inositides, sterol glycosides and other unidentified carbohydratesubstances.

The acetone-insoluble fractions of corn phosphatides employed incarrying out this invention may be associated with a carrier which maybe either a solid or a sterile liquid. The compositions containing theseactive ingredients may take the form of capsules, powders, tablets orother dosage forms which are particularly useful for oral ingestion.Liquid diluents are employed in sterile condition for oraladministration, and such a medium may be sterile water. The compositionsmay take the form of active material admixed with solid diluents and/ortableting adjuvants such as cornstarch, lactose, talc, stearic acid,magnesium stearate or gums. Any of the tableting materials used inpharmaceutical practice may be employed where there is noincompatibility with the acetone-insoluble fractions of cornphosphatides. When the compositions are employed in tablet form it ispreferred that the tablets be coated with the standard disintegratableor reabsorbable coatings which seal the tablet from air and moisture. Itis preferred to employ the therapeutic compositions containing the aboveactive ingredient in the usual capsule of gelatin or other availablematerials used in capsules, which are orally administered in that form.These compositions may also be sealed in air and moisture resistantpackets formed of heat-scalable synthetic resin sheets which may beopened when ready for administration and the contents orally ingested.Finally, the compositions may be introduced into sterile liquid vehiclesand maintained in suspension therein by means of the usualsurface-active agents employed for this purpose in the pharmaceuticalart.

The dosage unit forms of the acetone-insoluble fractions of corn andmaize phosphatides employed in carrying out this invention arecompounded to provide for oral administration, on the average, of threecumulative, sequentially administered doses daily. The preferred totaldaily dosage of the above active ingredients is the equivalent, in anamount by weight, of about 1.0 percent by weight of the average dailytotal fat intake of the patient being treated. The total daily dosage ofthe active ingredient is preferably about 1.0 gram, but a total dailydosage may be in the range of from about 1.0 gram to about 2.0 grams,and as much as a total of 3.0 grams daily may be administered. A totaldaily dosage larger than 2.0 grams of the active ingredient may beemployed, ifdesired, owing to the non-toxic properties ofthe. activeingredient, but such larger dosages are unnecessary .because thetherapeutic efiiciency of the treatment with these active ingredients isnot enhanced thereby.

The preferred total daily dosage of the active ingredients of 1.0 gramand total daily dosage in the range of 12 grams of active ingredients isprovided by the dosage unit forms; such as, for example, a capsule,tablet, packet or a measured amount of a suspension in a liquid. Eachdosage unit form contains, preferably, about 0.3 gram of theacetone-insoluble fractions of 'corn or maize phosphatides preparedaccording to Example I. The dosage unit forms may contain the activeingredients in an amount in the range of from 0.3 to 0.6 gram, or largerindividual doses may be administered simply by using more than onedosage unit form at a time. In the method of treating humans havingosteoarthritis, according to this invention, it is preferred toadminister, orally, No. capsules which each contain about 0.3 gram ofthe acetone-insoluble fractions of corn oil phosphatides, according tothe schedule of one capsule at a time three times daily to providecumulative sequential dosages.

The treatment of humans having osteoarthritis by oral administration ofthe above-described dosage unit form of a composition containing as theactive ingredient about 0.3 gram of the acetone-insoluble fractions ofcorn or maize phosphatides prepared according to Example 1 has beenclinically studied. These studies have established the efiicacy of theabove compositions and the method of employing them in treating humansso affiicted. An improvement in the condition of the patient is usuallyobserved within two to three weeks from the date the treatment iscommenced. Objective signs may then be noted which demonstrate theeffectiveness of the treatment. The pain experienced by the patient isalleviated. An obvious increase of motion is noted, as at the shoulderjoints. The most common result obtained is a demonstrable flexibility ofthe finger joints which permits a patient to resume fine movements; suchas, for example, piano playing, typewriting and knitting. Other resultsobtained which have been heretofore diflicult, if not impossible toaccomplish, are an increase in the mobility of the spine; improvedposture and carriage; and speed and freedom of movement in walking. Thespecificity of this treatment is evidenced by a recurrence of thesymptoms in almost every instance when the treatment is discontinued. Arelapse usually occurs within about two weeks; and, in some instances,within several months. In isolated cases there were no recurrences afterperiods of three and seven years. It has been observed that with theresumption of the treatment, the symptoms in the patient are eliminatedwithin about two or three Weeks after the treatment is resumed.

That the results obtained in the use of this therapy represent aspecific therapeutic effect of corn phosphatides, is evidenced by anumber of observed facts. Particularly impressive, has been the factthat improvement in mobility of the affected joints has been objectivelydemonstrable in these patients and has paralleled subjective reports.Further evidence of specificity include a more or less uniform intervalbetween start of treatment and evidence of improvement; high incidenceof relapses when treatment is discontinued, with invariable improvementafter its resumption; contrast between therapeutic efiects of thephosphatides obtained from corn and soybeans respectively; and completelack of efiect in other forms of arthritis.

The observed effects in the use of this therapy have appeared with arapidity and certainty never previously observed, with the possibleexception of the rapid symptomatic improvement noted with cortisone andits derivatives or analogues. These latter preparations, however,provoke so many deleterious side elfects, particularly in the aged, thattheir use is not recommended except by intraarticular injection. It isnoteworthy, moreover, that prior to thisinvention no specific treatment,aside from the foregoing use of steroids, has been available,therapeutic efforts having been limited to the prevention of posturaltrauma by weight-reduction, correction of obvious deformities byorthopedic procedures, improvement of mobility of joints byphysiotherapy, and relief of pain by analgesics, the most effective ofwhich, phenylbutazone, is too toxic to permit of prolongedadministration. On the basis of prior knowledge, therefore, the actionof these corn phosphatides has been unexpected, and the use of thismaterial appears to afford a physiological approach of great value tothe solution of this problem, both from the standpoint of treatment andas a promising avenue toward an understanding of the fundamentaletiology of this disease. While the corn phosphatides are knowncompounds and can be prepared by known methods, their therapeuticpotentialities have never before been investigated.

It is to be emphasized that the dosage and dosage forms outlined hereinare intended to be illustrative only and not restrictive. The amountsused have been chosen on the basis of clinical experience and areprobably minimal. Larger doses may be administered and still largerdoses may be used, if desired, since they are not harmful. It iscontemplated that these formulations may be varied or modified to aconsiderable extent without departing from the spirit of this invention;such as, for example, by employing of other methods of extraction,purification, or preservation; or by using of excipients, diluents, orflavorings in the compositions; or by including these corn phosphatidefractions in mixtures with vitamin, nutritional, or therapeutic agents;or by alteration of dosage form; such as, liquid tonics, elixirs, andlike preparations for oral use; or by admixing the corn phosphatidefractions with dietary items in therapeutically significant quantities.As outlined herein, the details of extraction, purification,preservation, and administration are intended to be illustrative, notrestrictive; and it is not intended, therefore, to limit this inventionto the specific embodiments herein set forth.

I claim:

1. A method of mitigating the symptoms of osteoarthritis in humans whichcomprises orally administering to a human having osteoarthritis doses ofat least about 0.3 gram of the acetone-insoluble fractions of thephosphatides of a grain selected from the group consisting of corn andmaize during the period in which said symptoms are exhibited by thehuman under treatment.

2. The method of claim 1 wherein the total daily dosage of saidacetone-insoluble fractions is approximately 1.0 percent by weight basedon the weight of the total daily fat intake of the human undertreatment.

3. The method of claim 1 wherein the total daily dosage of saidacetone-insoluble fractions is at least about 1.0 gram.

4. A method of mitigating the symptoms of osteoarthritis in humans whichconsists of administering orally to a human having osteoarthritiscumulative sequential doses of at least about 0.3 gram of theacetoneinsoluble fractions of the phosphatides of a grain selected fromthe group consisting of corn and maize, and maintaining said treatmentuntil the symptoms of osteoarthritis in the human under treatment arerelieved.

5. A method of mitigating the symptoms of osteoarthritis in humans whichcomprises orally administering to a human having osteoarthritissequential doses of from about 0.3 to about 1.0 gram of theacetone-insoluble fraction of the phosphatides of a grain selected fromthe group consisting of corn and maize during the period in which saidsymptoms are manifested.

6. The method of claim 5 wherein the total daily dosage provided by saidsequential doses of said acetoneinsoluble fractions is approximately 1.0percent by weight based on the weight of the total daily fat intake ofthe human to whom said sequential doses are orally administered.

7. An oral therapeutic composition in dosage unit form for mitigatingthe symptoms of osteoarthritis in humans having the disease comprisingfrom about 0.3 to about 1.0 gram of the acetone-insoluble fraction ofthe phosphatides of a grain selected from the group consisting of cornand maize per dosage unit and 'a pharmaceutical carrier.

References Cited in the file of this patent

7. AN ORAL THERAPEUTIC COMPOSITION IN DOSAGE UNIT FORM FOR MITIGATINGTHE SYMPTOMS OF OSTEOARTHRITIS IN HUMANS HAVING THE DISEASE COMPRISINGFROM ABOUT 0.3 TO ABOUT 1.0 GRAM OF THE ACETONE-INSOLUBLE FRACTION OFTHE PHOSPHATIDES OF A GRAIN SELECTED FROM THE GROUP CONSISTING OF CORNAND MAIZE PER DOSAGE UNIT AND A PHARMACEUTICAL CARRIER.